Noninvasive intracranial pressure monitoring throughout brain compliance guiding a ventriculoperitoneal shunt replacement in hydrocephalus-case report.

INTRODUCTION: Ventriculoperitoneal (VP) shunt is the primary therapy for hydrocephalus in children; however, this technique is amenable to malfunctions, which could be detected through an assessment of clinical signs and imaging results. Furthermore, early detection can prevent patient deterioration and guide clinical and surgical treatment. CASE PRESENTATION: A 5-year-old female with a premedical history of neonatal IVH, secondary hydrocephalus, multiple VP shunts revisions, and slit ventricle syndrome was evaluated using a noninvasive intracranial pressure monitor device at the early stages of the clinical symptoms, evidencing increased intracranial pressure and poor brain compliance. Serial MRI images demonstrated a slight ventricular enlargement, leading to the use of a gravitational VP shunt, promoting progressive improvement. On the follow-up visits, we used the noninvasive ICP monitoring device to guide the shunt adjustments until symptom resolution. Furthermore, the patient has been asymptomatic for the past 3 years without requiring new shunt revisions. DISCUSSION: Slit ventricle syndrome and VP shunt dysfunctions are challenging diagnoses for the neurosurgeon. The noninvasive intracranial monitoring has allowed a closer follow-up assisting early assessment of brain compliance changes related to a patient's symptomatology. Furthermore, this technique has high sensitivity and specificity in detecting alterations in the intracranial pressure, serving as a guide for the adjustments of programmable VP shunts, which may improve the patient's quality of life. CONCLUSION: Noninvasive ICP monitoring may lead to a less invasive assessment of patients with slit ventricle syndrome and could be used as a guide for adjustments of programmable shunts.

Spina bifida folate fortification in Brazil, update 2022: a cross-sectional study.

INTRODUCTION: Despite improving maternal-child indicators in Brazil, congenital malformations are still the second cause of mortality in the first years of life. This work aims to compare statistical data before and after flour fortification with folic acid (FA) in Brazil. METHODS: A cross-sectional Brazilian-population-based study compares the spina bifida (SB) rates pre- and post-fortification of the flour with folate. Data collected from the public database of the Live Birth Information System (SINASC/SUS) was performed. The period 1999-2004 (pre-fortification) was compared with 2005-2010 (post-maize and wheat fortification with FA), and another analysis comparing 2005-2010 and 2011-2020 (cassava flour fortification) was performed. The estimator was the prevalence ratio (PRR); the confidence interval selected was 95%. We used a random effects analysis model and inverse variance. RESULTS: The review showed a tendency to decrease the PRR after flour fortification; however, there is no statistical significance between studies. DATASUS data analysis comparing 5 years before and 5 years after mandatory maize and wheat flour fortification demonstrated a rate ratio of 1.05 (95% CI 0.99-1.1; p = 0.075). Furthermore, comparing 10 years after additional cassava flour folate fortification, the rate ratio increased to 1.4 (95% CI 1.34-1.45; p < 0.01). CONCLUSION: This study demonstrated an increase in SB after FA fortification. Possible explanations rely on national registry improvement, not fortified staple food, or further unidentified causes. Moreover, suggestions can be made for creating a mandatory registry for malformations, inspecting the concentrations of FA in the flour, and fortifying all food.

A hybrid simulation model for pre-operative planning of transsphenoidal encephalocele.

Congenital transsphenoidal encephalocele (CTE) surgical correction is a challenging procedure. Although rare, this anomaly, characterized with neural herniation elements, including the pituitary gland or optic pathway through the sphenoid bone with anatomical alteration, can be presented in many different ways and should be individually analyzed. Significant advances in medical technology and the 3D models may simulate the complex anatomical relations of the human body. Nowadays, medical education relies on the availability of standardized materials that can reliably emulate human anatomy. Therefore, realistic anatomical models have become an alternative for cadavers or animal specimens. In this technical note, the authors present a new technique to create personalized models that combine 3D printing, molding, and casting to create an anatomically and tactilely realistic model based on magnetic resonance and computerized tomography images. Produced from different silicon types, the model recreated the anatomic alterations precisely, allowing a multidisciplinary team to determine the adequate surgical approach for this patient. We describe a case of congenital transsphenoidal encephalocele of a 3-year-old boy, whose surgical correction was planned using a hybrid model. The technical description of the model is given in detail. This new hybrid model allowed a detailed discussion of the surgical approach aspects by having tissues of different consistencies and resistances and a very high prediction rate. This approach may allow a reduction in surgery time and possible complications after operative procedures.

Augmented reality and physical hybrid model simulation for preoperative planning of metopic craniosynostosis surgery.

OBJECTIVE: The main objective of neurosurgery is to establish safe and reliable surgical techniques. Medical technology has advanced during the 21st century, enabling the development of increasingly sophisticated tools for preoperative study that can be used by surgeons before performing surgery on an actual patient. Laser-printed models are a robust tool for improving surgical performance, planning an operative approach, and developing the skills and strategy to deal with uncommon and high-risk intraoperative difficulties. Practice with these models enhances the surgeon's understanding of 3D anatomy but has some limitations with regard to tactile perception. In this study, the authors aimed to develop a preoperative planning method that combines a hybrid model with augmented reality (AR) to enhance preparation for and planning of a specific surgical procedure, correction of metopic craniosynostosis, also known as trigonocephaly. METHODS: With the use of imaging data of an actual case patient who underwent surgical correction of metopic craniosynostosis, a physical hybrid model (for hands-on applications) and an AR app for a mobile device were created. The hybrid customized model was developed by using analysis of diagnostic CT imaging of a case patient with metopic craniosynostosis. Created from many different types of silicone, the physical model simulates anatomical conditions, allowing a multidisciplinary team to deal with different situations and to precisely determine the appropriate surgical approach. A real-time AR interface with the physical model was developed by using an AR app that enhances the anatomic aspects of the patient's skull. This method was used by 38 experienced surgeons (craniofacial plastic surgeons and neurosurgeons), who then responded to a questionnaire that evaluated the realism and utility of the hybrid AR simulation used in this method as a beneficial educational tool for teaching and preoperative planning in performing surgical metopic craniosynostosis correction. RESULTS: The authors developed a practice model for planning the surgical cranial remodeling used in the correction of metopic craniosynostosis. In the hybrid AR model, all aspects of the surgical procedure previously performed on the case patient were simulated: subcutaneous and subperiosteal dissection, skin incision, and skull remodeling with absorbable miniplates. The pre- and postoperative procedures were also carried out, which emphasizes the role of the AR app in the hybrid model. On the basis of the questionnaire, the hybrid AR tool was approved by the senior surgery team and considered adequate for educational purposes. Statistical analysis of the questionnaire responses also highlighted the potential for the use of the hybrid model in future applications. CONCLUSIONS: This new preoperative platform that combines physical and virtual models may represent an important method to improve multidisciplinary discussion in addition to being a powerful teaching tool. The hybrid model associated with the AR app provided an effective training environment, and it enhanced the teaching of surgical anatomy and operative strategies in a challenging neurosurgical procedure.

Multimaterial 3D printing preoperative planning for frontoethmoidal meningoencephalocele surgery.

INTRODUCTION: Surgical correction of frontoethmoidal meningoencephalocele, although rare, is still challenging to neurosurgeons and plastic reconstructive surgeons. It is fundamental to establish reliable and safe surgical techniques. The twenty-first century has brought great advances in medical technology, and the 3D models can mimic the correct tridimensional anatomical relation of a tissue organ or body part. They allow both tactile and spatial understanding of the lesion and organ involved. The 3D printing technology allows the preparation for specific surgery ahead of time, planning the surgical approach and developing plans to deal with uncommon and high-risk intraoperative scenarios. CASE PRESENTATION: The present report describes a case of frontoethmoidal encephalocele, (nasofrontal subtype) of a 19-month-old girl, whose surgical correction was planned using 3D printing modeling. CONCLUSION: The 3D model allowed a detailed discussion of the aspects of the surgical approach by having tissues of different consistencies and resistances, and also predicting with millimetric precision the bilateral orbitotomy measurements. Moreover, it was a fundamental and valuable factor in the multidisciplinary preoperative discussion. This approach allowed reducing the time of surgery, accurately planning the location of the osteotomies and precontouring the osteosynthesis material. 3D models can be very helpful tools in planning complex craniofacial operative procedures.

A new simulator model for knee arthroscopy procedures.

PURPOSE: Arthroscopy is currently the "gold standard" for various surgeries performed on the knee joint. Therefore, surgeons wishing to operate in this professional field should be able to perform this technique. Arthroscopic training, an experimental laboratory, is important for the surgeons' training, enabling them to increase their skills with the specific instruments and to become familiar with the operating techniques. The aim of this study was to present a new surgical simulator for training in arthroscopic procedures of the knee. METHODS: The Kneetrainer 1 is a simulator consisting of a type of thermo-retractile, thermo-sensitive synthetic rubber that has texture, colour, consistency, and mechanical resistance that mimic many human tissues. Nine simulators were used, operated by seventeen expert Brazilian surgeons in knee surgery. The surgeons performed arthroscopy, meniscectomy, and reconstruction of the anterior cruciate ligament (ACL), responded to an electronic questionnaire with several variables, and gave an overall score on the ability of the device to perform realistic simulation for the above procedures. RESULTS: The ability to perform the procedures of meniscectomy and ACL reconstruction was considered adequate by 82 and 100 % of the specialists, respectively. The overall scores for the ability to perform realistic simulation for the procedures meniscectomy and reconstruction of the anterior cruciate ligament by arthroscopy were 64.7 and 82.4 %, respectively. The simulator was therefore considered suitable for practical application with novice surgeons. CONCLUSION: The Kneetrainer 1 simulator was assessed as an effective tool for recreating accurate arthroscopic knee procedures. In addition, the simulator may be effective as a means of honing the skills of novice surgeons. Future investigations should be performed to validate the reliability of the simulator. LEVEL OF EVIDENCE: IV.

New anatomical simulator for pediatric neuroendoscopic practice.

INTRODUCTION: The practice of neuroendoscopic procedures requires many years of training to obtain the adequate skills to perform these operations safely. In this study, we present a new pediatric neuroendoscopic simulator that facilitates training. DESCRIPTION OF THE SIMULATOR: This realistic simulator was built with a synthetic thermo-retractile and thermo-sensible rubber called Neoderma® which, when combined with different polymers, produces more than 30 different formulae, which present textures, consistencies, and mechanical resistances similar to many human tissues. Silicon and fiberglass molds, in the shape of the cerebral ventricles, constitute the basic structure of the neuroendoscopic training module. The module offers the possibility for practicing many basic neuroendoscopic techniques such as: navigating the ventricular system to visualize important anatomic landmarks (e.g., septal and thalamostriate veins, foramen of Monro, temporal horns, aqueduct, and fourth ventricle), performing third ventriculostomy and choroid plexus cauterization, and resecting intraventricular "tumors" that bleed. CONCLUSION: It is important to emphasize that it is possible to perform with this simulator not only the rigid but also the flexible endoscopy, with good correspondence to reality and no risks. Notable future perspectives can be considered regarding this new pediatric simulator, for example, to improve the learning curve for nonexperienced neurosurgeons and to spread the flexible endoscopy technique.

Anatomical pediatric model for craniosynostosis surgical training.

INTRODUCTION: Several surgical training simulators have been created to improve the learning curve of residents in neurosurgery and plastic surgery. Laboratory training is fundamental for acquiring familiarity with the techniques of surgery and the skill in handling instruments. The aim of this study is to present a novel simulator for training in the technique of craniosynostectomy, specifically for the scaphocephaly type. DESCRIPTION OF THE SIMULATOR: This realistic simulator was built with a synthetic thermo-retractile and thermo-sensible rubber which, when combined with different polymers, produces more than 30 different formulas. These formulas present textures, consistencies, and mechanical resistance similar to many human tissues. Fiberglass molds in the shape of the skull constitute the basic structure of the craniosynostectomy training module. It has been possible to perform computerized tomography images due to the radiopacity of this simulator and to compare the pre- and postoperative images. RESULTS: The authors present a training model to practice the biparietal remodeling used in scaphocephaly correction. All aspects of the procedure are simulated: the skin incision, the subcutaneous and subperiosteal dissection, the osteotomies, and finally, the skull remodeling with absorbable microplates. The presence of superior sagittal sinus can simulate emergency situations with bleeding. CONCLUSION: The authors conclude that this training model can represent a fairly useful method to accustom trainees to the required surgical techniques and simulates well the steps of standard surgery for scaphocephaly. This training provides an alternative to the use of human cadavers and animal models. Furthermore, it can represent the anatomical alteration precisely as well as intraoperative emergency situations.

A new device to treat ping-pong skull fractures: The hammer puller technique. A comparative analysis using a realistic simulation model.

Background: This study aims to describe a new surgical technique for the treatment of ping-pong skull fractures and to evaluate its efficacy in a realistic simulation model compared to the dissector elevation technique. Methods: A total of 64 fractures were obtained using 16 model units, each with four fractures (two frontal and two parietal). The hammer puller technique was applied for left-sided fractures and the dissector technique for right-sided fractures. The variables evaluated were fracture repair time, fracture volume, fracture corrected volume, and fracture correction percentage. Fractures were separated into groups according to the surgical technique used (hammer or dissector) and the bone fractured (frontal or parietal). Statistical analysis was performed with Jamovi® software (version 2.3) using Student's t-test. Results: A complete degree of fracture correction was achieved with both techniques, demonstrating a sufficient performance in the correction of the deformity. The hammer technique was shown to be faster in correcting frontal bone depressions with 20.1 ± 7.8 s compared to 31.3 ± 4.7 s for the dissector technique, P < 0.001. There was no statistically significant difference for parietal applications (P = 0.405). Conclusion: This study describes a new minimally invasive surgical technique for the treatment of ping-pong fractures. Comparative analysis showed that both techniques were equally effective but that the hammer puller technique was more efficient than the dissector elevation technique, especially for frontal bone fractures.

Development and Evaluation of a Mixed Reality Model for Training the Retrosigmoid Approach.

BACKGROUND: The use of simulation has the potential to accelerate the learning curves and increase the efficiency of surgeons. However, there is currently a scarcity in models dedicated to skull base surgical approaches. Thus, the objective of this study was to develop a cost-effective mixed reality system consisting of an ultrarealistic physical model and augmented reality and evaluate its use in training surgeons on the retrosigmoid approach. METHODS: The virtual models were developed from images of patients with vestibular schwannoma. The tumor was mirrored to allow bilateral approaches and the model has drawers for repositioning structures, allowing reuse of the material and cost reduction. Pre and posttest assessments were applied to 10 residents and young neurosurgeons, divided into control and test groups. Only the control group was exposed to the model. The difference in scores obtained by participants before and after exposure to the models was considered for analysis and participants in the control group answered self-satisfaction questionnaires. RESULTS: The mean differences were 4.80 in the control group (95% credibility intervals=1.08-9.79) and 5.43 in the test group (95% credibility intervals=1.67-8.20). The average score of the self-satisfaction questionnaires was 24.0 (23-25). CONCLUSIONS: The ultrarealistic model efficiently allowed retromastoid access to the cerebellopontine angle. A tendency toward greater gains in performance in the group exposed to the model was verified. Scores from the self-satisfaction questionnaires demonstrated that participants considered the model relevant for neurosurgical training and increased confidence among surgeons.

Torque Teno virus DNA is found in the intracranial aneurysm wall-Is there a causative role?

Objective: Torque Teno virus (TTV) is a recently discovered virus with high prevalence worldwide, that has been associated with vascular diseases. The aim of this study is to investigate the prevalence of TTV molecular DNA in the intracranial aneurysm (IA) artery walls. Method: Samples of IA walls were collected after microsurgical clipping from 35 patients with IA (22 ruptured/13 unruptured cases). The samples were submitted to molecular DNA extraction using the EasyMag automatized extractor and performed with Qiagen DNA extraction Minikit 250. The samples underwent PCR examination with primers for ß-globin as internal control using the Nanodrop ® 2000 spectrophotometer. A quantitative (real-time) PCR with TTV-specific primers was performed. Clinical and radiological data of patients included was collected. Results: TTV was detected in 15 (42.85%) cases, being 10 (45.4%) ruptured and 5 (38.4%) unruptured (p = 0.732) lesions. Multiple IAs accounted for 14 (40%) cases. Five cases (17.2%) had TTV+ and multiple aneurysms (p = 0.73). Association between presence of virus and aneurysm rupture was not statistically significant (p = 0.96). Conclusion: This study demonstrated a relatively high prevalence of viral DNA in the walls of IAs. This is the first study to identify the presence of TTV DNA in IA's samples, which was found more often in ruptured lesions. This is an exploratory study, therefore, larger studies are required to clarify the relationships between inflammation, viral infection, IA formation and rupture.

Three-Dimensional Printing in Minimally Invasive Cardiac Surgery: Optimizing Surgical Planning and Education with Life-Like Models.

Over recent years, the surgical community has demonstrated a growing interest in imaging advancements that enable more detailed and accurate preoperative diagnoses. Alongside with traditional imaging methods, three-dimensional (3-D) printing emerged as an attractive tool to complement pathology assessment and surgical planning. Minimally invasive cardiac surgery, with its wide range of challenging procedures and innovative techniques, represents an ideal territory for testing its precision, efficacy, and clinical impact. This review summarizes the available literature on 3-D printing usefulness in minimally invasive cardiac surgery, illustrated with images from a selected surgical case. As data collected demonstrates, life-like models may be a valuable adjunct tool in surgical learning, preoperative planning, and simulation, potentially adding safety to the procedure and contributing to better outcomes.

The Potential Applications of Augmented Reality in Fetoscopic Surgery for Antenatal Treatment of Myelomeningocele.

OBJECTIVE: To develop a preoperative planning method using augmented reality (AR) of a specific surgical procedure: fetoscopy for myelomeningocele repair. METHODS: Imaging data were acquired of a pregnant woman at 27 weeks of gestation whose fetus was diagnosed with myelomeningocele. The patient was identified as a candidate for fetoscopic repair of the spine defect, and an AR application for mobile device simulation was developed. The virtual customized model was created by analysis of the presurgical magnetic resonance imaging. A real-time AR interface was developed by using an application that enhanced the anatomical aspects of both mother and fetus. RESULTS: A virtual model for planning fetoscopy repair for myelomeningocele was developed. Preoperative and postoperative procedures were successfully carried out, emphasizing the beneficial role of the AR application. The use of the AR model allowed the multidisciplinary team to engage in discussion to determine the appropriate surgical approach. It also allowed a clearer explanation of the procedure to the parents enabling a better understanding of the parents regarding specifics characteristics of their baby's spine defect. CONCLUSIONS: This new preoperative platform using a virtual model represents an important tool to improve patient's comprehension, multidisciplinary discussion, and surgical planning. In addition, it can be used worldwide as a teaching tool in the fetal surgery field.

Quality assessment of a new surgical simulator for neuroendoscopic training.

OBJECT: Ideal surgical training models should be entirely reliable, atoxic, easy to handle, and, if possible, low cost. All available models have their advantages and disadvantages. The choice of one or another will depend on the type of surgery to be performed. The authors created an anatomical model called the S.I.M.O.N.T. (Sinus Model Oto-Rhino Neuro Trainer) Neurosurgical Endotrainer, which can provide reliable neuroendoscopic training. The aim in the present study was to assess both the quality of the model and the development of surgical skills by trainees. METHODS: The S.I.M.O.N.T. is built of a synthetic thermoretractable, thermosensible rubber called Neoderma, which, combined with different polymers, produces more than 30 different formulas. Quality assessment of the model was based on qualitative and quantitative data obtained from training sessions with 9 experienced and 13 inexperienced neurosurgeons. The techniques used for evaluation were face validation, retest and interrater reliability, and construct validation. RESULTS: The experts considered the S.I.M.O.N.T. capable of reproducing surgical situations as if they were real and presenting great similarity with the human brain. Surgical results of serial training showed that the model could be considered precise. Finally, development and improvement in surgical skills by the trainees were observed and considered relevant to further training. It was also observed that the probability of any single error was dramatically decreased after each training session, with a mean reduction of 41.65% (range 38.7%-45.6%). CONCLUSIONS: Neuroendoscopic training has some specific requirements. A unique set of instruments is required, as is a model that can resemble real-life situations. The S.I.M.O.N.T. is a new alternative model specially designed for this purpose. Validation techniques followed by precision assessments attested to the model's feasibility.

Realistic simulator for craniosynostosis endoscopic approach.

Craniosynostosis is a premature fusion of cranial sutures, and it requires surgery to decrease cranial pressure and remodel the affected areas. However, mastering these procedures requires years of supervised training. Several neurosurgical training simulators have been created to shorten the learning curve. Laboratory training is fundamental for acquiring familiarity with the necessary techniques and skills to properly handle instruments. This video presents a novel simulator for training on the endoscopic treatment for scaphocephaly and trigonocephaly, covering all aspects of the procedure, from patient positioning to performing osteotomies. The video can be found here: https://vimeo.com/512526147.

The historic evolution of intracranial pressure and cerebrospinal fluid pulse pressure concepts: Two centuries of challenges.

BACKGROUND: There is a consensus on the importance of monitoring intracranial pressure (ICP) during neurosurgery, and this monitoring reduces mortality during procedures. Current knowledge of ICP and cerebrospinal fluid pulse pressure has been built thanks to more than two centuries of research on brain dynamics. METHODS: Articles and books were selected using the descriptors "ICP," "cerebrospinal fluid pulse," "monitoring," "Monro-Kellie doctrine," and "ICP waveform" in electronic databases PubMed, Lilacs, Science Direct, and EMBASE. RESULTS: Several anatomists and physiologists have helped clarify the patterns of intracranial volumes under normal and pathological conditions. Monro-Kellie doctrine was an important step in a story that is reconstructed in this article. Through documentary research, we report the contribution of important medical figures, such as Monro, Kellie, Abercrombie, Burrows, Cushing, Langfitt, Marmarou, and other physiologists and anatomists who left their marks on the history of Medicine. CONCLUSION: Understanding intracranial dynamics is an unfinished historical construction. Current knowledge is the result of two centuries of research that began with the investigations of Alexander Monro secundus.

Spinal cord tumor leading to urinary retention resulting from Schistosoma mansoni infection in a child.

Schistosomose mansoni is an endemic disease in Brazil. It rarely affects the central nervous system, particularly in children. We report the case of a child that presented with an acute spinal cord compression condition, resulting from a mass that proved to be a granuloma caused by a Schistosoma mansoni infection. Proper treatment had no effect on the regression of urological symptoms and the child had to undergo a Mitrofanoff principle.

Preoperative Planning Modalities for Meningoencephalocele: New Proof of Concept.

OBJECTIVE: Late surgical correction of meningoencephalocele is a rare scenario that remains challenging for surgeons. Three-dimensional models can mimic the correct anatomical relationships, and technological systems have brought advances to medicine. This study aims to present a novel preoperative planning modality that combines augmented reality with a hybrid model for complex malformation associated with late correction. METHODS: The present report describes a case of frontoethmoidal encephalocele of a 10-year-old girl. Two different methods for planning the approach were developed: 1) a hybrid hands-on model and 2) augmented reality, using a cell phone app and headset display. The customized hybrid model was created based on patient's imaging. The augmented reality app was developed with a real-time interface. RESULTS: The hybrid model recreated anatomic alterations, thereby allowing a multidisciplinary team to determine an appropriate surgical approach. All aspects of the surgical procedure were simulated. A pre- to postoperative comparison was made, which emphasized benefit of tridimensional anatomical relationships using augmented reality tool and its role in preoperative planning. CONCLUSIONS: The authors believe this new multimodality preoperative platform could be a useful method to improve multidisciplinary discussion as well as a powerful tool for teaching and planning.

Human herpesvirus DNA occurrence in intracranial aneurysmal wall: illustrative case.

BACKGROUND: Subarachnoid hemorrhages secondary to intracranial aneurysms (IAs) are events of high mortality. These neurological vascular diseases arise from local and systemic inflammation that culminates in vessel wall changes. They may also have a possible relationship with chronic viral infections, such as human herpesvirus (HHV), and especially Epstein-Barr virus (EBV), which causes several medical conditions. This is the first description of the presence of HHV deoxyribonucleic acid (DNA) in a patient with IA. OBSERVATIONS: A 61-year-old woman with a downgraded level of consciousness underwent radiological examinations that identified a 10-mm ruptured aneurysm in the anterior communicating artery. A microsurgery clip was performed to definitively treat the aneurysm and occurred without surgical complications. Molecular analysis of the material obtained revealed the presence of EBV DNA in the aneurysm wall. The patient died 21 days after admission due to clinical complications and brain swelling. LESSONS: This is the first description of the presence of herpesvirus DNA in a patient with IA, presented in 2.8% of our data. These findings highlight that viral infection may contribute to the pathophysiology and is an additional risk factor for IA formation, progression, and rupture by modulating vessel wall inflammation and structural changes in chronic infections.